VCP/p97 regulates Beclin-1-dependent autophagy initiation

Hill, Sandra Malmgren,1987Gothenburg University,Göteborgs universitet,Institutionen för neurovetenskap och fysiologi, sektionen för psykiatri och neurokemi,Institute of Neuroscience and Physiology, Department of Psychiatry and Neurochemistry (author)

Autophagy is an essential cellular process that removes harmful protein species, and autophagy upregulation may be able to protect against neurodegeneration and various pathogens. Here, we have identified the essential protein VCP/p97 (VCP, valosin-containing protein) as a novel regulator of autophagosome biogenesis, where VCP regulates autophagy induction in two ways, both dependent on Beclin-1. Utilizing small-molecule inhibitors of VCP ATPase activity, we show that VCP stabilizes Beclin-1 levels by promoting the deubiquitinase activity of ataxin-3 towards Beclin-1. VCP also regulates the assembly and activity of the Beclin-1-containing phosphatidylinositol-3-kinase (PI3K) complex I, thus regulating the production of PI(3)P, a key signaling lipid responsible for the recruitment of downstream autophagy factors. A decreased level of VCP, or inhibition of its ATPase activity, impairs starvation-induced production of PI(3)P and limits downstream recruitment of WIPI2, ATG16L and LC3, thereby decreasing autophagosome formation, illustrating an important role for VCP in early autophagy initiation.

NATURVETENSKAP Biologi Biokemi och molekylärbiologi hsv//swe
NATURAL SCIENCES Biological Sciences Biochemistry and Molecular Biology hsv//eng
valosin-containing protein
beclin 1
mammalian autophagy
atpase
vcp
clearance
p97
degradation
multiple
cell
Biochemistry & Molecular Biology

Wrobel, L. (author)
Ashkenazi, A. (author)
Fernandez-Estevez, M. (author)
Tan, K. (author)
Burli, R. W. (author)
Rubinsztein, D. C. (author)
Göteborgs universitetInstitutionen för neurovetenskap och fysiologi, sektionen för psykiatri och neurokemi (creator_code:org_t)

In:Nature Chemical Biology: Springer Science and Business Media LLC17, s. 448-4551552-44501552-4469

By the author/editor: Hill, Sandra Mal ...; Wrobel, L.; Ashkenazi, A.; Fernandez-Esteve ...; Tan, K.; Burli, R. W.; show more...; Rubinsztein, D. ...; show less...

About the subject

NATURAL SCIENCES: NATURAL SCIENCES; and Biological Scien ...; and Biochemistry and ...

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